Therapeutic composition

ABSTRACT

A therapeutic composition comprised of an aqueous medium containing about 75-150 millimoles of Na , about 5-50 millimoles of K , about 5-50 millimoles of HCO3 , about 75-150 millimoles of Cl and preferably containing about 1-30 millimoles of Mg and about 1-30 millimoles of HPO4 and/or SO4 ; the solution having a pH of about 5.95-8.4 and an osmolality of about 170-460 and preferably about 260-340 and more preferably 290-310. The solution can be administered orally but preferably parenterally. Also, the anhydrous form of the composition in a tablet form as well as an oral composition containing flavoring agents is taught.

, United States Patent 1191 11 3,821,368 Reynolds 1*June 28, 1974 [5 THERAPEUTIC COMPOSITION 2,265,453 12/1941 Schmidt 424/128 3,337,404 8/1967 P 11' t l 424/153 [75] Invent Beverly Reymlds, Dallas 3,356,570 12/1967 13316 11 61 424/153 [73] Assignee: Cybersal, Inc., Dallas, Tex, 3,676,553 7/1972 Reynolds 424/128 1 Notice: The portion of the of this Primary Examiner-Stanley J. Friedman g g zfi (tiovjuly 1989 Attorney, Agent, or FirmClegg & Cantrell and as een 1sc aime Crisman v [22] Filed: July 21, 1972 [21] Appl. N0.: 273,701 [57] ABSTRACT Related Us. Application Data A therapeutic composition comprised of an aqueous V medium containing about 75- 1150 millimoles of Na", [63] f;ff :2 ;;,,;j;?; i about 5-50 millimoles of Kt about 5-50 millimoles 0f Ser. 1 16. 885,295jDeC. 15, 1969, Pat. N0. 3,676,553. CO3? about 75-150 millimoles of c1- and P bly containing about 1-30 millimoles of Mg and [52] us. Cl 424/128, 424/153, 424/154, about m les of HPO f and/or so the 424/156 solution having a pH of about 5.95 8.4 and an osmo- 51 Int. Cl A6lh 27/00 lality of about 170460 and Preferably about 260440 5 Field of Search 424/128 153 154 1 2 and more preferably 290-310. The solution can be administered orally but preferably parenterally. Also, the [56] References Cited anhydrous form of the composition in a tablet form as UNITED STATES PATENTS well as an oral composition containing flavoring agents is taught. r r 233,063 10/1880 Boughton 424/128 2,224,252 12/1940 Callaway 99/1 7 Claims, 1 Drawing Figure PA'IENTEB JUN 28 [974 q O O O 4 3 2 log pH 8 E R E S CALCULATED POINTS THERAPEUTIC COMPOSITION BACKGROUND OF THE INVENTION This application is a continuation-in-part of my copending US. application Ser. No. 149,081 filed June 1,

1971 entitled Method For Administering Water Soluble Drugs, Nutrients and Other Solutes to. a Mammal now abandoned which is in turn a continuation-in-part of my earlier filed US. application Ser. No. 885,295 filed Dec. 15, 1969, now US. Pat. No. 3,676,553.

After accidental or' elective .operative injury to human patients, there occurs a decrease in the hemoglobin concentration, an elevation of the erythrocyte sedimentation rate of peripheral blood, and a loss of red blood cells (RBC) from the effective blood volume.

niques of increasing complexity, is exposed to body water infusates which are at variance, frequently extreme, with the physicochemical content in health.

Altering ionic content of water solutions has not provided the water environment considered optimal during elective or traumatic operative therapy. Furthermore, synthetic water solutions should provide support to the patient in excess of maintenance of blood water volume. Water for injection, sterile, U.S.P., may be used to replace or expand blood water lost during elective or accidental trauma, if the sole purpose of administered water solution is the replacement of water losses. However, the anemia of injury is more intense in the post-operative period after use of sterile water or Trademark of Abbott Laboratories, North Chicago. Illinois Trademark of Cutler Laboratories. Berkeley 10, California "'Trademark of Baxter Laboratories, Inc., Morton Grove, Illinois correct these adversities. These are administration of ,fusion. In recent years, synthetic water solutions, with or without protein, have been used to re-establish nor malcy in peripheral vascular volumes and for maintenance of blood pressure.

The development of synthetic water solutions in the prior art has emphasized ionic content, particularly sodium chloride, with little regard to other physicochemical requirements. Such thinking is still current. The

most recently introduced water solutions beg their use through ionic contents equivalent to plasma water as the latter appears during health. Also, the blood water of patients, receiving a multitude of new anesthetic agents and adjuvants and subjected to operative techof other similar hypo-osmolar solutions, resulting in These events are g ed a m a- Also. lmmedlprolonged morbidit particularly in post-operative ately subsequent to the in ury the white e Co 18 hospital time, and accounting for the more frequent use usually ele ated. and the thrombocyte ount I 8- of whole blood before, during, and after operation. creased, implicating pancytlc mechanisms. The addition of solium chloride to sterile water, in

The administration of whole blood is useful to rectify 20 SQ-called i t i concentration (154 E /L i|- the pa yt ng s- However. most su g ns ha liequivalents/literl), has reduced only minimally the been unable to maintain adequate quantities of perlphpost-operative anemia. Such a solution has enhanced eral total hemoglobin, red blood cells, and thrombowater retention significantly, as evidenced by consiscytes through the use of whole blood, even when quantent gain in weight during operation when saline is adtities far in excess of that lost by bleeding are infused. ministered. Complementing normal saline solutions Also, the collection and storage of whole blood generwith potassium and calcium in concentrations equivaally produces a hyperosmolar, acidic water solution, as lent to plasma water (10 mEq/L, total) has had little a result of the changes in RBC and blood water during additional effect. Hence, the addition of ions to sterile collection and storage. Furthermore, whole blood is exwater in quality and at concentrations approximately pensive, and may produce unwanted immunohethose in blood water has not significantly reduced anematological responses in the recipient. mias observed from the use of sterile water alone.

The surgeon and anesthesiologist generally have four Examples of parenterally administrable preparations other choices, i.e., instead of whole blood infusion, to in current use are:

Approximate CatiommEq/L) AnionmEqllL) Solution pH Na K Mg Ca Cl Phosphate l-ICO Acetate Gluconate Lactate Human Plasma 7.4 140 4-5 2-3 5 102 2.5 27 5 Normosol R ll'm 7.4 140 5 3 9s 21 23 Laclatcd Ringer's 6.5 4 .l 109 28 Normal Saline 5.4 154 I54 Dextrose 5% in saline 4.6 154 154 Polysal" 6.2 10 3 10 103 5s Plasma-Lyte*** 6.2 140 to 3 s 103 47 8 Certain of these solutions are compared in specific tests with applicants aqueous solution.

SUMMARY OF THE INVENTION DESCRIPTION OF THE DRAWING FIG. 1 is a graphical presentation of results obtained during hemorrhaging and solution replacement tests performed on canines with solutions formulated in accordance with the invention, and illustrates the influence on results of the pH parameter of the invention.

The administrable solution can have an osmolality (defined as the product of the activity coefficient of each species times the quantity in millimoles dissolved in 1 liter of water) within the range of from about l70 to DESCRIPTON OF THE PREFERRED 5 about 460, preferably from 260 to 340, more prefera- EMBODIMENTS bly from 290 to 3l0 and most preferably about 300. Applicants therapeutic composition is preferably The PH can desrahly l i from about to about iso osmolar with respect to the mean osmoality of 8.4 and preferably 18 within the range of 6.8 to 8.2 and ECW. The mobility osmolality of the ions is preferably more preferably about to about The most maximal in the ECW to minimize ICW (intracellular 10 ferred range is between about 7.9 and about 7.6. It water) depletion or overload. Also, the water content not that the HPO; be pres is preferably representative of the ratio of water to 501- emhut it 15 ph q ere stablliaation of solute veute loss during the Operative procedure or trauma of locitles, thus d1str1but1on,is desired in the ECW and/or imbalance ICW. Known water soluble salts containing the above In extracellular water, the major Cations are 15 ions are useful to make up the solution in U.S.P. water. 1 and whereas the major anions are Examples of such salts include NaCl, KCl, NaHCO on: M0,: or, so,=, nro, and 10A (imperme- KHCOQ Mgclzi M2504, NaQHPO Mgsoi and able organic anions). The relative size of the hydrated K2HPO4' ions, as references to K, and the velocity of each ion A Preferred cqhposmon for phhehteral admmstra' in water, in a if electrical field, tion is one containing about millimoles of NaHCO velomy ofsoute ion about 17 millimoles of KCl, about 103 millimoles of under gradient f one Relative NaCl and about 5 millimoles of MgSO Solute Solute volt/cm (univalent ion) of s gl t e ibn Solution? having an osmolality less man about 290 cation anion or 05 volt/cm (divalent) Angstmms can be designed to move into the cells; thus, such solu- 25 tions are useful in treatment of heat stroke. However, :1 5 2 8 if the osmolality desired is in excess of about 310, the solution can be designed to attract water out of the i I73 cells. As a result, such solutions are useful, for example, g? :3 8:3; in the treatment of overdoses of barbituates or any situlOA 35 L84 ation resulting in an unusual accumulation of water M 1 6 3; Q33 hin the cells, ca 4 ,5 The pH of the solution is desirably between about 5.95 and about 8.4. Within this broad range, it is preferred that the pH be within about 6.8 to about 8.2 and The mobility coefficient of each ion in dilute water more Preferred to hold the P between about solution is dependent upon the size of the hydrated ion to about The most preferhed range is between and upon its velocity under a uniform electrical gradiabout to about P levels the ranges Set forth ent. Changes in solute content, pH, and osmolality afare Preferably Obtained y using the pp p Salts f t h mobility ffl i t The p and taught within this invention, and such solution will be $0,, ions are implicated as components of intercellu- 40 g y buffered against P chahges- Adjustment of the lar water or interstitial water substrates during glycoly- P Cah he Obtained if desired, with known acids sis of oxidative reaction sequences in energy metabobases, 'i L 2 m NKOH, 2 gas, Whose [i reactions with the solution will not produce ion solutes I Applicants parenteral solution contains sodium different from those specified- (Na and potassium (K*) as the principal major cation The solution is preferably administered parenterally; solutes, and bicarbonate (HCO and chloride (Cl') but, it can be administered orally. Where oral adminisas th primary anion l Th were l d b tration is desired, the salt components are desirably cause h i oeffi ient of bili i h h d chosen to eliminate objectionable taste of the solution. (14*) and hydro l (OI-l), are m i l i h respect to For example, KCl can impart a bad taste. A more acall other solutes, in any given situation. Magnesium ceptable solution from the standpoint of taste is one (Mg was selected as the principal minor solute catin g 3, a, g z and 2 4- ion, and phosphate (l-lPOf) and/or sulfate (SOf) andvoting agents, e.g., orange flavoring, etc. and pharma- /or gluconate or other organic anions as the principal ceutically acceptable vitamins in dosage form compatiminor solute anion. The Mg, HPO, and S0,, ions ble with applicants composition can be incorporated. assist in stabilization of solute velocities, hence distri- For example, vitamin C is useful where the solution is bution, in the extracellular water and/or the intracellutaken orally. Other additives pharmaceutically acceptlar water. The concentration of the ions in applicants able and compatible with applicants composition can aqueous solution are given in millimoles as: also be incorporated.

' 1 Most lon Minimum Maximum Preferred Preferred ,Sodium (Na*) 150 -140 12% Potassium (K*) 5 50 10-40 l7 Magnesium (Mg) 1 30 2-20 5 Phosphate (HOP.\") or Sulfate ($0 or Organic ions l 30 220 5 Bicarbonate (HCO;,') 5 50 [0-40 25 Chloride (CF) 75 150 85-130 Also, the appropriate amount of cations andanions can be contained in the anhydrous form as well as a concentrated hydrous form. The hydrous form can be at a concentration more than the desired osmolality and, before administration, it can be diluted to the desired osmolality. By containing the solution at a high ion concentration, shipping charges, storage costs, etc. can be reduced.

Regarding the anhydrous form, the appropriate salts and. the desired amounts of salts can be contained in a protective container (a pharmaceutically acceptable container) so that the convenient dilution to the desired volume and at the desired place of usage can be obtained. Also, the salts can be compressed in a uniform mixture and can optionally contain an inert diluent, e.g., binder. Thus, the salts can be embodied in a tablet suitable for dilution and eventually oral administration.

The tablet binder is a pharmaceutically acceptable binder and is preferably one that produces minimum osmotic effects and is one that is not ionized. Examples of useful binders include nonionic detergents 'such as Pluronic F-68 (trademark of Wyandotte Chemicals Corp., defined as a condensate of ethylene oxide with a condensate of propylene oxide and propylene glycol) and similar nonionic detergents, preferably having molecularweights above about 8,000. Also, the tablet can contain pharmaceutically acceptable effervescent agents such as citric acid, tartic acid, etc. Where the salts are in the anhydrous form, the concentration of the ions can be (mole percent):

Preferred Where the Mg and I-IFO, and/or S0 ions are absent, the molar composition can be about S7.S46.9% Na", about 31.l-l2.5% K", about 3.l-12.5% HCO3", and about 46.9-37.5% Cl. But, preferably, the Mg and HPO, and/or S0,, are present.

Applicants solution is preferably administered to mammals before operation, during anesthesia, during operation and after operation or trauma. Desirably, it is administered in quantities calculated to replace water and osmolar losses in the ECW. Excessive administration of the solution can be tolerated by the mam'- mal, however, over-expansion of the ECW can modify moble cell mobilization. Preferably, the solution is administered before trauma and in amounts calculated to replace water and osmolar losses in the ECW. Where administered before operation and before anesthesia, it is preferably begun about 2 hours prior .to anesthesia.

Proper administering of applicants solution, inter alia, can have the following benefits:

1. iso-osmolar expansion of ECW with predictable equilibration of administered water between circulating water volume and ISW (Interstitial Water) space components of ECW;

2. As a result of l a high tolerance of unplanned overloading of the circulating water volume-thus 6 hypertension, cardiac pulmonary failure and coma can be reduced;

3. As a result of l maintenance of suspension indices of solutes, e.g., mobile cells, lipids, and proteins, in ECW is obtained;

4. as a result of l) and (3), iso-osmolar expansion of large solutes in ECW is obtained;

5. as a result of (4), minimization of mobile cell destruction (particularly red cell) and of intravascular aggregation of cells is obtainedboth of which otherwise follow planned or unplanned trauma;

6. as a result of l enhancement of perfusion of tissues during elective, operative, and, anesthetic trauma, with or without prior accidental trauma, is reduced.

A material benefit which flows. from the use of the applicants solution is a reduction in the amount or volume of solution which must be administered, as compared to other prior art parenterallly administerable solutions, in order to obtain the desired physiological results. In most instances and'for most purposes, the volume of applicants solution which is desirably administered is approximately the same as the volume of liquid lost during operation or trauma. This contrasts quite favorably with the consensus of opinion on good practice with lactated Ringers solution, which consensus directs that approximately four times the liquid lost should be replaced with lactated Ringers solution, and with the consensus with regard to normal saline solution, which consensus directs that approximately twice the lost volume should be replaced.

Other benefits are obvious after the specification and claims are read and fully understood.

The following examples are presentedmerely to teach specific working embodiments of the invention. Equivalents and uses, obvious to those skilled in the art, are intended to be incorporated within the invention as defined in the specification and appended claims.

. EXAMPLE Mongrel canines having a mean weight of 15 kgm were operated on under pentobar'bital sodium anesthesia for bilateral placement of ligatures about the renal pelvi and/or for splenectomy. Seven days after opera-' tion, these animals were exposed to water loading. For water depletion testing, no renal ligatures were placed. The aortic blood pressure, the hermatocrit (HCT), blood water volume (BlW), and extracellular water volume (ECW) were determined before and after either loading or deprivation, and at indicated times. Where a control patent is used, neither loading nor deprivation was effected and a lapse of time equal to the same lapse for either loading or deprivation was allowed for the after determination. Where loading experiments were done, 30 minutes were allowed between the determinations. In depletion experiments determinations were made immediately after hemorrhage, at 2 hours post hemorrhage, and at 5 days post hemorrhage. The PV (or BlW) was'measured with T- 1824 dye, also defined as Evans blue dye; 30 minutes was allowed for equilibration of the dye. I-ICT was determined from multiple arterial and venous microhematocrit determinations (corrected for trapped plasma) and was related to the true or total body he-' matocrit by the ratio 0.85 -this ratio was empirically measured by comparing direct red cell volume and blood water measurements-in 2S canines. Red cell mass 7 (RBC) was calculated from the hematocrit and blood water volume. ECW was measured with radiobromium, Br-82, 2 hours was allowed for equilibration of the isotope. Interstitial water (ISW) was determined as the difference between ECW and TBV. Osmolality was determined by commercial osmometer. Specific gravities of all water solutions either added or removed were determined, thus specific correlations were established between the weight of either added or removed fluids. The partial pressure of water vapor in the ambient air was adjusted to the partial pressure of water vapor in the expired air of the animal under evaluation. During loading, the ligatures were tightened about the renal pelvi. Therefore, after the minute interval for distribution of added water solutions, during the 2 hours a1- 8 TABLEI Comparison of applicants solution with other water solutions (all values 1 hour after replacement of water solution equal to shed blood volume) of an additional 16 percent of RBC. Survival was reduced markedly in all animals receiving other water solutions. Regarding other water solutions. enhancement of TBV was best with sodium chloride. but pH and RBC qeqrs sssionttiby at tglpw, ry m ypH and RBC alterations by other water solutions decreased survival. Furthermore, there is no statistical difference between animals receiving either no water lreplacement or either lactated Ringers solution or Acetate Ringers solution. These results are reported in lowed for equilibration of isotope and 30 mlnutes for Table I:

TABLE I CONDITION TBV HCT RBC BIW ISW ECW Percent Mortality, 24 Hours Steady State Before Deprivation 1050 44 465 585 2670 3720 47% Hemorrhage 555 31 165 390 2590 3145 100, W/O Water replacement "53 35 62 93 85 After Applicant's Solution 800 31 235 565 2840 3640 Zero (0%) pH 7.6 *76 51 97 106 98 300 m O/L 495 ml After Sodium Chloride 820 18 I48 672 2912 3732 80 pH 5.5 *78 32 115 109 100 308 mO/L 495 ml After Lactated Ringer's and/or Normosol-R 570 23 150 420 3639 4209 90 pH 6.5 *54 32 72 136 113 260 mO/L 495 ml After Polysal and/or Plasma-Lite 615 26 160 455 3030 3645 75 pH 6.7 *58 34 78 114 98 280 mO/L 495 ml Percent of Steady State "mO/l millimoles/liter equilibration of the dye, water losses from the animals were minimized.

All solutions were prepared on the day of use after;

during water deprivation of the ECW by hemorrhage at 47 percent of the TBV. In one series, no replacement. water solution was administered, and, as reported in Table I, no animals survived 24 hours; these animals expiring secondary to cardiac and pulmonary arrest. In four additional series, applicants solution (U.S.P. water containing 25 millimoles of NaHCO l7 millimoles of KCL, 103 millimoles of NaCl and 5 millimoles of MgSO osmolality 300 pH 7.6 7.8) and certain other water solutions were infused singly into the canines at the onset of ventricular fibrillation and cardiac arrest. The infused qualities were equal to the shed blood volume. Survival was 100 percent in animals receiving applicants solution,with a mobilization EFFECT OF VARYING OSMOLALITIES OF APPLICANTS SOLUTION DURING WATER DEPRIVATION Table 11 indicates the effect of varying the osmolality of applicants solutions (pH 6.8 8.2) upon the mortality of canines after water deprivation through hemorrhage of 47 percent of steady state TBV. A 47 percent hemorrhage was sufficient to produce death in percent of the canines in the absence of injection of parenteral fluids. The replacement of applicants solution is equal to shed blood:

TABLE II A RBC Mass After The above data clearly indicates basis for preferred osmolality ranges, especially the 290-310 range.

. 9 ESTABLISHMENT OF pH RANG Five canines to each of 10 series were observed during separate water deprivation tests of hemorrhage of 47 percent of TBV. The exact quantity of shed TBV was replaced at the onset of cardiac arrest with sodium chloride and sodium bircarbonate mixtures at pH in range of from 5.5 to 8.8. Although these solutions are not the same as applicants solution, these data obtained are applicable with their invention. The preferred pH established with minimum mortality, i.e., no mortality, is from 6.8 to 8.2.

Additional pHrange data was developed by water deprivation tests of hemorrhage of approximately 47 percent of TBV using multiple series of three and five ca-l nines. The same procedures as set forth above were fol-' lowed; the exact quantity of shed TBV was replaced at the onset of cardiac arrest with solutions having pHs between 6.2 and 9.2. The solutions were made by altering the pH of a solution having the following makeup and having a pH initially adjusted to 7.5:

Each 100 ml. contains:

Sodium Chloride U.S.P. 0.66 gm.

- Sodium Bicarbonate U.S.P. 0.15 gm. Potassium Chloride U.S.P. 0.10 gm. Magnesium Sulfate Heptahydrate U.S.P. 0.12 gm.

Water for Injection U.S.P. Balance The pH was adjusted by addition of either HCI or NaOH to the particular levels employed in the test series.

One hundred percent mortality was encountered when there was no replacement after hemorrhage of 47-50 percent TBV. The further results of this test are presented in the graph of FIG. 1. In FIG. 1, the vertical axis presents mortality percentages on a logarithmic scale. The horizontal axis in FIG. 1 is calibrated in terms of log pH.

The curve drawn on the graph of FIG. 1 includes a,

dashed portion at the low pH portion of the curve. The dashed portion represents a conservative extrapolation of the data observed a pHs 6.2, 6.5, and 6.8 in order to obtain pH valves at the 50 percent mortality rate (LD and the 100 percent mortality rate.

From FIG. 1 it can be seen that the minimum mortality-in this test series, zero mortalitywas observed with solutions having pHs between about 6.8 and about 8.2. FIG. 1 also shows that on the high pH side, 100 percent mortality was observed with solutions having pHs of about 8.8, while the extrapolated curve on the low pH side indicates that the 100 percent mortality level would be reached at a pH of approximately 5.3. The importance of pH, at least in situations involving 10 slope of the curve at each end of the pH range. The 50 percent mortality rate (LD On the low pH side is crossed at about pH 5.95, and on the high pH side at a pH of about 8.4. While in most instances persons making use of the invention would far prefer to use solutions with pHs within the ranges which the foregoing tests show to produce zero mortality, the data on FIG. 1 shows that solutions somewhat more acid and somewhat more basic also have utility, and can be used to advantage, especially in situations involving less trauma than removal of 47-50 percent of TBV. For these rea- I sons, the 50 percent mortality rate levels are regarded as defining the outer marks of the preferredpH range for solutions of the invention.

While the foregoing discussion has emphasized the importance of pH, and has presented data developed from severe trauma testing on canines to illustrate its importance, it should be understood that the criticalityof pH as a parameter of the invention is not of the same order of importance as that of other parameters of the invention, such as osmolality. The reasons for the relatively lower importance of pH as a solution parameter lie in the fact that under most circumstances the quantity of solution administered to make up for lostliquid is small, and in the fact that the human blood stream, and the human water system taken as a whole, are inherently good self buffering systems. The first point can be appreciated by noting that in typical surgery, the total liquid loss runs in the neighborhood of 7-10 percent of TBV, which is far less thzanthe approximately 47 percent blood loss involved in the canine test series just discussed. The second point can be appreciated if it is remembered that the human blood stream is rapidly self-buffering in the neighborhood of about 7.5.

' The practical significance of these facts for purposes of 9 a a ine ssnd t WATER. LOADING Each of 15 canines in three differentseries were observed during water loading with (1 aqueous solutions of chloride, (2) aqueous solutions of sodium bicarbonate and (3) applicants aqueous solution containing 25 millimoles of NaHCO 17 millimoles of KCI, 103 millimoles of NaCl and 5 millimoles of MgSO The mean ECW of the canine 3,000 ml. Results of the tests are given in Table TABLE III WATER SOLUTION ADMINISTERED ECW AFTER INFUSION. ICW' RBC MASS Percent Percent Percent TBV percent Increase Change Water Increase or Water Volume Decrease mO/L Volume, ml Total, ml Volume Osmolality mO/L ECW A. Aqueous Solution of Sodium Chloride 290 600 3610 20.3 O.66 298 0 Decrease 5.2 300 600 3605 20 0.45 299 0 Decrease 1*: 1.2 310 600 3798 26.6 1.66 295 6.6 Decrease 6.4 B. Aqueous Solution of Sodium Bicarbonate 290 600 3625 20.8 0.71 297 O Decrease 1.6 300 600 3656 21.5 +0.15 302 0 Increase 1.5 310 600 3710 23.4 +015 301 3.6 Decrease 3.3

C. Applicant's Aqueous Solution 1 300 600 3600 20 0 300 0 Increase 20 severe trauma such as was present in the t e s t seriesuncler discussion, both on the high side and on the low side, can be observed from FIG. 1 by noting thesteep n The above data indicate that with applicants solution the ECW was expanded by the same increment as the load and there was neither an increase nor decrease in LOADING AT DIFFERENT OSMOLALITIES AND pH Loading of ECW with applicants solution at different osmolalities and pH was effected. The loading was equal to 100 percent of TBV. The infused solutions contain Na", K*, Cl and HCO; as the primary components and Mg, HPO and $0., as minor components (3-I0 millimoles) at the indicated osmolalities and pH. Results are indicated in Table VI:

TABLE IV CONDITION TBV HCT RBC BlW ISW ECW Percent Mortality at 24 Hours Steady State 1100 44 485 615 3900 5000 Before Loading After A licants SoIu'ti ii 1320 44 585 735 4800 61 20 Zero pH 7.6 +20 +20 +20 +23 +20 300 m/L After Sodium Chloride I160 37 435 725 5300 6460 pH 5.5 a +5 l7 -17 +18 +36 +29 308 mO/L(Normal saline) After Lactated Ringer's and/or Normosol-R l I 37 432 703 49 I 5 6050 Zero pH 6.5 260 mO/L After Polysal and/or Plasma-Lyte I128 39 440 788 4932 6060 Zero pH 6.7 +3 II II +28 +27 +22 230 m0/L 35 The above data indicate that with sodium chloride, TABLE VI the RBC was reduced 17 percent, and 20 percent of the canines expired. The other solutions produced no mor- Osmolality 7 Change Percent tality, however, each produced dislocations of water (mo/L) PH ECW RBC Mmallty and solutes and reduction in RBC as compared to ap- 40 300 73 +225 +22 Zero plicants solution (identified in Water Loading tests, 70 2 +1 2 go. O. osmolality 300). (L8 9 3 do 260 7.8 +l5 5 do. EFFECT ON BLOOD PRESSURE WITH 63 0 m 290 7.3 +20 +10 do. APPLICANT S SOLUTION (L8 +19 3 do. During water loading and water deprivation tests, the Z-g :52 i g 3:- effect on the aortic and femoral blood pressures were 340 0 observed. Results of these tests are indicated in Table 460 g-g 11g g:- V. Applicants aqueous solution is identical to the one +57 identified in Water-Loading tests.

What is claimed is:

1. An injectable acqueous solution comprising about to about millimoles of sodium cation, about 5 to about 50 millimoles of potassium cation, about 5 to about 50 millimoles of bicarbonate anion and about 75 to about 150 millimoles of chloride anion and having a pH of about 5.95 to about 8.4 and an osmolality of about 290 to about 310.

2. The composition of claim 1 wherein the osmolality is about 300.

3. The composition of claim 1 wherein about 1 to about 30 millimoles of magnesium cation and from about I to about 30 millimoles of phosphate and/or sulfate anion are incorporated into the composition.

4. The aqueous solution of claim 1 wherein there is incorporated about 1 to about 30 millimoles of magnesium cation.

5. The aqueous solution of claim 1 wherein there is incorporated about l to about 30 millimoles of phosphate anion or sulfate anion or a combination of phosphate and sulfate anions.

6. An injectable aqueous solution comprised of about 85 to about 140 millimoles of sodium cation, about to about 40 millimoles of potassium cation, about 2 to about millimoles of magnesium cation, about 85 to about 130 millimoles of chloride anion, about 10 to about 40 millimoles of bicarbonate anion and about 2 to about 20millim0les of phosphate and/or sulfate anion(s) and the solution having a pH within the range of anion and about to about millimoles of chloride anion and having an osmolality of about 290 toabout 310, and a pH insufficiently different from that of the system into which it is to be injected to materially alter the system pH. i 

2. The composition of claim 1 wherein the osmolality is about
 300. 3. The composition of claim 1 wherein about 1 to about 30 millimoles of magnesium cation and from about 1 to about 30 millimoles of phosphate and/or sulfate anion are incorporated into the composition.
 4. The aqueous solution of claim 1 wherein there is incorporated about 1 to about 30 millimoles of magnesium cation.
 5. The aqueous solution of claim 1 wherein there is incorporated about 1 to about 30 millimoles of phosphate anion or sulfate anion or a combination of phosphate and sulfate anions.
 6. An injectable aqueous solution comprised of about 85 to about 140 millimoles of sodium cation, about 10 to about 40 millimoles of potassium cation, about 2 to about 20 millimoles of magnesium cation, about 85 to about 130 millimoles of chloride anion, about 10 to about 40 millimoles of bicarbonate anion and about 2 to about 20 millimoles of phosphate and/or sulfate anion(s) and the solution having a pH within the range of about 5.95 to about 8.4 and having an osmolality within the range of about 290 to about
 310. 7. An acqueous solution for injection into a mammal comprising about 75 to about 150 millimoles of sodium cation, about 5 to about 50 millimoles of potassium cation, about 5 to about 50 millimoles of bicarbonate anion and about 75 to about 150 millimoles of chloride anion and having an osmolality of about 290 to about 310, and a pH insufficiently different from that of the system into which it is to be injected to materially alter the system pH. 